1040-5488/14/9112-1419/0 VOL. 91, NO. 12, PP. 1419Y1429 OPTOMETRY AND VISION SCIENCE Copyright * 2014 American Academy of Optometry
ORIGINAL ARTICLE
Correlation between Tear Osmolarity and Tear Meniscus Carlos Garcı´a-Resu´a*, Hugo Pena-Verdeal*, Beatriz Remeseiro†, Maria J. Gira´ldez†, and Eva Yebra-Pimentel‡
ABSTRACT Purpose. To examine the relationship between tear meniscus height (TMH) and subjective meniscus grading (subjective tear meniscus [TM]) with tear osmolarity. Methods. Tear osmolarity measurements (using TearLab) and digital images of the TM were obtained in 177 consecutive patients undergoing an eye examination at our optometry clinic (Universidad de Santiago de Compostela, Spain) who fulfilled the study’s inclusion criteria. Participants were also administered the McMonnies and Ocular Surface Disease Index questionnaires for the detection of dry eye disease. The lower TM was videotaped by a digital camera attached to a slit lamp in its central portion without fluorescein instillation. After the study, a masked observer extracted an image from each video and measured the TMH using open source software (NIH ImageJ). Subsequently, the masked observer subjectively graded the appearance of each meniscus. For statistical analysis, subjects were stratified by age and by dry eye symptoms as indicated by their scores in the two questionnaires. Results. In the whole study population, a significant relationship was observed between osmolarity and TMH (r = j0.41, p G 0.001) and osmolarity and subjective TM (r = 0.35, p G 0.001). A cluster analysis revealed similar correlations when subjects were stratified by age or dry eye symptoms, these correlations being more pronounced in older and more symptomatic subjects. Objective TMH measurements and subjective meniscus quality were also correlated (r = j0.75, p G 0.001). Conclusions. Osmolarity and both objective TMH measurements and subjective interpretation of the meniscus showed high correlation, especially in older symptomatic subjects. (Optom Vis Sci 2014;91:1419Y1429) Key Words: osmolarity, tear meniscus, TearLab osmometer, ImageJ software
D
ry eye disease (DED) is a common condition that causes discomfort and visual distortions. The characteristic features of DED are changes in tear film composition and inflammation of the ocular surface.1Y4 An abnormally high tear film osmolarity induces inflammatory events that negatively affect ocular surface cells,1Y5 leading to symptoms such as eye irritation and blurred vision with impacts on quality of life.4,6Y8 Dry eye disease is also the main reason why subjects stop wearing contact lenses.6 There are a variety of diagnostic tools available for DED. Most methods are based on assessing symptoms and include *OD, MSc † OD, MSc, PhD ‡ OD, PhD Department of Applied Physics (Optometry Group GI-2092), University of Santiago de Compostela, Santiago de Compostela, Spain (CG-R, HP-V, MJG, EY-P); and Departamento de Computacio´n, Universidade da Coruna, Campus de Elvin˜a s/n, A Corun˜a, Spain (BR).
questionnaires like the McMonnies or the Ocular Surface Disease Index (OSDI), which have been adapted for the detection of DED.9,10 Other tests commonly used are the Schirmer test, tear film break-up time, meibomian secretion scoring, and sodium fluorescein and lissamine green staining of the cornea and conjunctiva.11Y13 However, many of these tests are invasive or require eye manipulation, which could destabilize the tear film.14 The method proposed here, measuring tear meniscus height (TMH), provides a noninvasive indication of the total volume of the tear film.15 Tear meniscus height is routinely measured by eye care practitioners through slit-lamp biomicroscopy.11,16 Reported mean TMH values for healthy eyes range from 0.14 to 0.46 mm,17Y30 depending on the technique used17,21Y25 and the different end points used.19Y22,26Y30 The most widely used method involves image capture of the meniscus using a camera attached to a slit lamp, and TMH measurements may be quantified by software assistance.31,32 ImageJ33 is a free domain image analysis tool that
Optometry and Vision Science, Vol. 91, No. 12, December 2014
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1420 Tear Osmolarity and Tear MeniscusVGarcı´a-Resu´a et al. TABLE 1.
Subjective classification of the meniscus scheme Grade
Group
Description
1
Intact
2 3
Slightly diminished Markedly diminished or discontinuous
4
Absent
Meniscus of variable height and regular shape. Absence of debris Regular, but less visible. Absence of debris Diminished meniscus of irregular shape. Presence of debris Invisible meniscus
quantifies features viewed in a picture.34 This software helps interpret TMH data by enhancing resolution and hence the repeatability of measurements.34 In routine clinical practice, TMH is often measured using a graticule eyepiece attached to a biomicroscope.19,21,24,25,27 However, using this method, it is difficult to distinguish the upper limit of the tear meniscus (TM) during eye movement.29 This has determined that many clinicians prefer subjective assessment of the TM appearance, or TM quality, over TMH measurements.35 The main factors determined during TM assessment are the presence/absence of debris and/or foaming, its regularity (whether the top forms a regular or irregular line), and an estimate of height36,37 (Table 1). Tear fluid hyperosmolarity is a common feature to all types of DED. Normal tear film osmolarity is 302 T 6.3 mOsm/l,38Y40 whereas a mean of 321 mOsm/l is reported for DED.39 The most commonly used cutoff for a diagnosis of DED is 316 mOsm/l,39,41 which provides a sensitivity of 73% and a specificity of 90%.41
Grades 1 and 2 represent healthy meniscus Grades 3 and 4 represent abnormal meniscus
Hyperosmolarity has been described by the Tear Film and Ocular Surface Society Dry Eye Workshop as one of the main mechanisms of DED,4 being the main cause of discomfort, ocular surface damage, and inflammation.1,3,38,42 This has meant that tear film osmolarity measurement is considered the gold standard for DED diagnosis.2,4Y6,40,43,44 One of the main dilemmas when trying to make a diagnosis of DED is the poor correlation between dry eye tests,23,45 along with a lack of correlation between symptoms and objective signs.46 Osmolarity is defined as the number of dissolved solute particles in 1 kg of solution, regardless of particle shape, size, density, configuration, or charge.5 Hence, a higher osmolarity will induce a greater amount of evaporation from the eye surface and thus reduce tear film volume. Given the TM holds some 75 to 90% of the total tear film volume,15 any reduction in TMH should indicate an increase in tear film osmolarity. This study was designed to examine the relationship between TMH and osmolarity using the TearLab electric impedance osmometer to
FIGURE 1. Example of how TMH is measured by the ImageJ software. A color version of this figure is available online at www.optvissci.com. Optometry and Vision Science, Vol. 91, No. 12, December 2014
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Tear Osmolarity and Tear MeniscusVGarcı´a-Resu´a et al.
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TABLE 2.
Descriptive statistics
McMonnies OSDI Osmolarity TMH Subjective TM
Mean/ median
SD/IQR
Minimum
Maximum
6.00 8.33 305.68 0.20 1.00
3.00Y13.00 4.17Y17.71 14.37 0.06 1.00Y2.00
0.00 0.00 275.00 0.06 1.00
33.00 64.58 357.00 0.36 4.00
DED questionaires (McMonnies and OSDI) and subjective TM are dimensionless parameters. Osmolarity is indicated in milliosmoles per liter and TMH is indicated in millimeters. Mean and SD for parametric variables; median and interquartile range (IQR) for nonparametric variables. n = 177.
determine osmolarity and a new software tool to measure TMH. Subjective interpretation of TM appearance was also compared with objective TMH and osmolarity determinations. In addition, a cluster analysis was performed to examine the effects on the correlations observed of age and of symptoms expressed as the scores obtained in two dry eye grading questionnaires (OSDI and McMonnies).
METHODS Subjects and Procedures One hundred seventy-seven consecutive patients (78 male, 99 female) with a mean (TSD) age of 25.92 (T12.03) years (range, 18 to 65 years) were recruited among subjects visiting the Optometry Clinic of the Optometry Faculty (Universidad de Santiago de Compostela, Spain) for an eye examination. Subjects were excluded if they had a history of conjunctival, scleral, or corneal disease; prior eye surgery; glaucoma; diabetes mellitus; or a thyroid disorder or wore contact lenses. Qualifying subjects were administered two DED questionnaires (OSDI and McMonnies) and scheduled for another visit for tear osmolarity and meniscus height measurements. No participant was under any type of medication or used artificial tears at the time of the testing session. The study protocol adhered to the tenets of the Declaration of Helsinki and was approved by the Ethics Committee of the University of Santiago de Compostela (Spain). Only the right eye was examined because of induced excess tearing in the second eye and to avoid overstating the precision of statistical estimates.47 All measurements were performed between 5 PM and 6 PM. Throughout the study, laboratory conditions of temperature, light, and humidity were kept constant (temperature, 20 to 23-C; relative humidity, 50 to 60%).
DED Questionnaires The questionnaires at the screening visit were OSDI6,10,48 and McMonnies grading DED questionnaires,6,9,49,50 which established the symptoms statement of the patient.
Ocular Surface Disease Index The OSDI (Allergan Inc, Irvine, CA)51 is a 12-item selfadministered questionnaire designed for rapid assessment of ocular surface symptoms related to chronic DED, severity, and their effects on the patient. Total OSDI scores were calculated
FIGURE 2. Correlation between osmolarity and TM variables in the whole study population. (A) Correlation between osmolarity and TMH (Pearson test). (B) Correlation between osmolarity and subjective TM (Spearman Q test). (C) Correlation between TMH and subjective TM (Spearman Q test).
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1422 Tear Osmolarity and Tear MeniscusVGarcı´a-Resu´a et al. TABLE 3.
Descriptive statistics for the age rangeYstratified groups e20 y (n = 88) Age range Age McMonnies OSDI Osmolarity TMH Subjective TM
Q45 y (n = 22)
Between 20 and 45 y (n = 67)
Mean/median
SD/IQR
Mean/median
SD/IQR
Mean/median
SD/IQR
18.93 4.50 8.33 303.93 0.21 1.00
0.85 3.00Y7.00 4.17Y12.50 15.76 0.05 1.00 Y 2.00
30.83 6.00 10.42 304.80 0.20 1.00
6.39 4.00Y12.00 4.17Y18.75 12.01 0.051 1.00Y2.00
54.18 20.00 31.25 315.41 0.18 2.00
6.27 15.00Y27.25 16.66Y43.23 11.55 0.08 1.00Y3.00
DED questionaires (McMonnies and OSDI) and subjective TM are dimensionless parameters. Age is indicated in years, osmolarity is indicated in milliosmoles per liter, and TMH is indicated in millimeters. Mean and SD for parametric variables; median and interquartile range (IQR) for nonparametric variables.
according to published guidelines,10,51 and a score of 13 or more was established as the cutoff for DED.6,10,48
OSDI ¼
Sum of Scores 25 Number of Questions Answered
McMonnies Subjects completed a modified McMonnies dry eye questionnaire to assess dryness symptom number, type, and frequency.52 This 12-item questionnaire elicits information about recent medical and medication history that could affect tear production. Symptoms included in the questionnaire are eye soreness, scratchiness, dryness, and grittiness (from the original McMonnies questionnaire) along with burning, stinging, foreign body sensation, and itchiness. As in prior studies, a cutoff of 14.549,50 was used to differentiate between normality and mild to severe DED.
Tear Meniscus Height Video Capture and Image Selection Meniscus videos were recorded by a Topcon DV-3 digital camera attached to the slit lamp and stored using Topcon IMAGEnet i-base at a spatial resolution of 1024 768 pixels in the RGB color space. Subjects seated at the slit lamp were instructed to look at a target positioned to induce primary eye gaze and a natural blink. The TM was acquired centrally (at the 6-o’clock position) (Fig. 1) with magnification set at 500 (objective 40, ocular 12.5; without fluorescein). To avoid reflex tearing, a short moderate-illumination light beam (3 mm wide, 5 mm height) was used to prevent the light shining directly into the pupil during measurements.19 In total, 177 TM images extracted from recorded videos were examined. Images were selected from the recordings at the point when a fully expanded stable meniscus was observed after the blink. A blinded observer then measured TMH by computerassisted image analysis and outgrowth size was quantified using ImageJ software v1.47i (National Institutes of Health, Bethesda, MD; http://imagej.nih.gov/ij/).33 Subsequent to TMH measurement, the observer assigned a subjective classification category to each central meniscus.
Objective Measurement of TMH The TM was measured according to defined criteria19,34 in its central portion (at 6 o’clock) as the distance between the darker
edge of the lower eyelid and the upper limit of the TM using ImageJ. The TMH was marked using the straight tool, which allows the user to draw a line (Fig. 1) in the middle of the illuminated area perpendicular to the eyelid margin, from the lowest meniscus limit to the highest one. Next, the height of the TM was calculated according to the software pixels, which were transformed into millimeters as 300 pixels = 1 mm. This conversion factor was previously calculated for our camera.
Subjective Meniscus Grading The appearance of the meniscus was also graded according to the criteria described in Table 1, whereby grades 1 and 2 indicate a healthy or control meniscus and grades 3 and 4 represent an abnormal meniscus. The grading scale was based on that published by Khurana et al.36 and later modified by Garcia-Resua et al.19 This evaluation was performed on the image obtained for the central TM using the slit lamp (Fig. 1).
Osmolarity: TearLab Osmometer The TearLab Osmometer (TearLab Corp, San Diego, CA) was used to measure the osmolarity of the tear film.5,53 The subject was seated with the chin tilted upward and eyes directed toward the ceiling. The instrument probe (housing the disposable microchip) is then placed on the lower TM until a beep is emitted, indicating that the tear sample has been collected. Only a 0.05-Kl tear sample is needed and measurements are directly made on the TM using the probe, which takes up the sample through capillary action.2,12,13 The TearLab quickly (in less than 10 seconds) converts the electrical impedance of the sample into osmolarity in milliosmoles per liter, which is displayed on the device screen. Its measurement range is 275 to 400 mOsm/l.
Statistical Analysis After confirming their normal distribution using the KolmogorovSmirnov test, numerical data (osmolarity and TMH) were compared using parametric tests. Nonparametric tests were used for McMonnies scores, OSDI scores, and subjective TM grades. Numerical variables are provided as means and their SD, whereas nonparametric variables are expressed as medians and interquartile ranges.
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FIGURE 3.
FIGURE 4.
Correlation between osmolarity and TM variables in subjects aged 20 years or younger. (A) Correlation between osmolarity and TMH (Pearson test). (B) Correlation between osmolarity and subjective TM (Spearman Q test). (C) Correlation between TMH and subjective TM (Spearman Q test).
Correlation between osmolarity and TM variables in subjects aged 20 to 45 years. (A) Correlation between osmolarity and TMH (Pearson test). (B) Correlation between osmolarity and subjective TM (Spearman Q test). (C) Correlation between TMH and subjective TM (Spearman Q test).
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1424 Tear Osmolarity and Tear MeniscusVGarcı´a-Resu´a et al.
To examine the effects of age and DED symptoms on correlations between variables, a cluster analysis was also performed on three data sets: & Whole study population: 177 subjects (N = 177). & Subjects stratified by age: 25 years or younger (n = 88), 25 to 45 years (n = 67), and 45 years or older (n = 22). & Subjects stratified by symptoms: a score indicating DED in both questionnaires (n = 104), a score indicating DED in one questionnaire (n = 40), and a score indicating the absence of DED in both questionnaires (n = 33). Relationships were assessed through Pearson correlation for parametric data and through Spearman Q for nonparametric data. Correlations between variables were described as weak (0.2 to 0.4), moderate (0.4 to 0.6), fairly good (0.61 to 0.8), or strong (0.8 to 1.0).50,54 All statistical tests were performed using the software package SPSS v. 19.0 for Windows (SPSS Inc, Chicago, IL). Significance was set at p e 0.05.
RESULTS Whole Study Population Descriptive statistics for the whole study population (N = 177) are provided in Table 2. In our subjective TM evaluation, most subjects showed an intact (n = 109) or slightly diminished (n = 45) meniscus. An abnormal TM was detected in 29 subjects in whom the meniscus was described as markedly diminished or discontinuous and in 2 subjects lacking a meniscus. Fig. 2 shows the correlation between osmolarity and both the objective and subjective TM data recorded for the study group. Osmolarity was moderately negatively correlated with TMH (r = j0.41, p G 0.001) and weakly positively correlated with subjective TM quality (r = 0.35, p G 0.001). As expected, strong negative correlation was observed between TMH and TM quality (r = j0.75, p G 0.001), indicating that the worse the subjective meniscus quality, the smaller the objective TMH measurement.
Stratification by Age
FIGURE 5. Correlation between osmolarity and TM variables in subjects aged 45 years or older. (A) Correlation between osmolarity and TMH (Pearson test). (B) Correlation between osmolarity and subjective TM (Spearman Q test). (C) Correlation between TMH and subjective TM (Spearman Q test).
Descriptive statistics for the subjects stratified into three age groups are provided in Table 3. As for the whole study population, osmolarity was correlated with both subjective meniscus quality and objective TMH for each age range. In all age groups, osmolarity was inversely related to TMH, and correlation was greater with age. Thus, correlation was weak for the younger subject group (r = j0.28, p = 0.01) (Fig. 3A) and moderate for the older groups (G45 years, r = j0.40, p = 0.001, and 945 years, r = j0.52, p = 0.014; Figs. 4A and 5A). Correlation between osmolarity and TM quality was weak to fairly good depending on age (from r = 0.27 for e20 years to r = 0.63 for Q45 years, all p G 0.012) (Figs. 3B, 4B, and 5C). When examining TMH and TM quality, significant correlation was observed (p G 0.001 in all cases) ranging from fairly good (r = j0.69 for subjects aged e20 years to r = j0.75 for subjects aged 20 to 45 years) (Figs. 3C and 4C) to strong (r = j0.90 for subjects aged Q45 years)
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Tear Osmolarity and Tear MeniscusVGarcı´a-Resu´a et al.
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TABLE 4.
Descriptive statistics for the symptom assessmentYstratified groups Fail no questionnaire (n = 104) Age McMonnies OSDI Osmolarity TMH Subjective TM
Fail one questionnaire (n = 40)
Fail two questionnaires (n = 33)
Mean/median
SD/IQR
Mean/median
SD/IQR
Mean/median
SD/IQR
20.81 4.00 6.25 302.26 0.21 1.00
3.64 3.00Y6.00 2.08Y8.33 14.17 0.05 1.00Y2.00
25.93 10.00 16.67 308.60 0.20 2.00
12.60 6.00Y13.00 14.58Y22.92 14.75 0.06 1.00Y2.00
42.03 17.00 29.17 312.92 0.15 2.00
14.37 15.00Y25.50 19.79Y40.63 11.04 0.07 1.00Y3.00
DED questionaires (McMonnies and OSDI) and subjective TM are dimensionless parameters. Age is indicated in years, osmolarity is indicated in milliosmoles per liter, and TMH is indicated in millimeters. Mean and SD for parametric variables; median and interquartile range (IQR) for nonparametric variables.
(Fig. 5C) such that greater objective and subjective TM data were better correlated in older subjects.
Stratification by Symptoms Descriptive statistics for the subjects stratified according to their questionnaire scores are provided in Table 4. Figs. 6 to 8 illustrate correlations among the variables examined detected in each of the three symptom groups. Once again, TMH versus osmolarity and TMH versus TM quality were negatively correlated, whereas positive correlation was detected between osmolarity and TM quality. For nonsymptomatic subjects (scores in both questionnaires indicated no DED), correlation between osmolarity and meniscus variables was very weak for both the objective (TMH) (r = j0.19, p = 0.049) (Fig. 6A) and subjective (TM quality) (r = 0.08, p = 0.4) (Fig. 6B) assessments. In subjects with mild symptoms (scores in one questionnaire indicated DED), this relationship was moderate in both comparisons (r = j0.48, p = 0.002 for osmolarity vs. TMH; r = 0.51, p G 0.001 for osmolarity vs. TM quality) (Fig. 7A, B). Finally, when only strongly symptomatic subjects were considered (scores in both questionnaires indicated DED), osmolarity correlations with both the objective (r = j0.52, p = 0.002, for osmolarity vs. TMH, Fig. 8A) and subjective (r = 0.64, p G 0.001 for osmolarity vs. TM quality, Fig. 8B) meniscus variables were slightly improved over those observed in the subjects with mild DED symptoms. Correlations between objective TMH and subjective TM quality measurements were fairly good in nonsymptomatic subjects (r = j0.60, p G 0.001) (Fig. 6C) and strong in those with mild or severe symptoms (r = j0.81, p G 0.001 or r = j0.90, p G 0.001, respectively; Figs. 7C and 8C). Thus, correlations became stronger with increasing symptoms.
DISCUSSION In this study, we detected an expected statistically significant relationship between osmolarity and TMH (Fig. 2) such that higher osmolarity values (indicating poorer tear film quality) give rise to lower TMH values. This trend was also observed in the cluster analysis (Figs. 3 to 8), whereby osmolarity and TMH showed improved correlation when one questionnaire indicated DED and even better correlation when both questionnaires
identified dry eye symptoms. This suggests that correlations between these tear film tests are more pronounced in symptomatic subjects. In addition, when the study population was stratified by age, better correlation between the two variables was noted in the older subjects. In agreement with this finding, Glasson et al.50 detected a lower TMH in symptomatic intolerant contact lens wearers than control subjects. These authors also noted that TMH correlated negatively with osmolarity (Pearson correlation for meniscus height [mm] vs. osmolarity [mOsm/kg] was r = j0.566, p = 0.014 and r = j0.438, p = 0.047 for two subject groups).50 On the contrary, Nichols et al.46 detected no correlation between TMH and symptoms of dry eye. However, TMH was measured using the variable beam height on the slit-lamp biomicroscope, which is a less precise method and much more influenced by subjective errors and interpretation than the image analysis method used here. Several authors have related higher osmolarity values to tear film abnormalities, which lead to symptoms and discomfort.14,38Y40,55 Moreover, a lower TMH appears to induce similar symptoms in patients with different forms of DED20,56,57; thus, we would expect higher osmolarity values in subjects with lower meniscus heights. When the TM was subjectively graded, significant correlation was also found between a higher osmolarity and worse meniscus quality. This relationship was significant and gained in strength as subject age and dry eye symptoms increased. Finally, when we compared objective TMH measurements with subjective interpretations of meniscus quality, good to strong correlation was observed between subjective meniscus assessment and TMH (Figs. 2 to 8). This determined that for lower TMH values measured using software assistance, an experienced observer graded the TM as worse, and again stronger correlation was shown in older and more symptomatic subjects. This finding is consistent with the results of a previous study in which we measured TMH using a graticule eyepiece.19 Accordingly, based on objective TMH measurements, a meniscus picture scale could be designed to help clinicians grade the TM. Few studies have addressed the relationship between osmolarity and TMH,25 and even fewer have considered the subjective interpretation of the TM. Using the TearLab osmometer, tear osmolarity can be easily and quickly measured. However, the method has two important shortcomings: methods based on the electric impedance principle are less repeatable than freezing pointYbased techniques,41 and
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1426 Tear Osmolarity and Tear MeniscusVGarcı´a-Resu´a et al.
FIGURE 6.
FIGURE 7.
Correlation between osmolarity and TM variables in subjects whose scores in two questionnaires indicated the absence of dry eye. (A) Correlation between osmolarity and TMH (Pearson test). (B) Correlation between osmolarity and subjective TM (Spearman Q test). (C) Correlation between TMH and subjective TM (Spearman Q test).
Correlation between osmolarity and TM variables in subjects whose scores in one questionnaire indicated dry eye. (A) Correlation between osmolarity and TMH (Pearson test). (B) Correlation between osmolarity and subjective TM (Spearman Q test). (C) Correlation between TMH and subjective TM (Spearman Q test).
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Tear Osmolarity and Tear MeniscusVGarcı´a-Resu´a et al.
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each TearLab measurement is quite expensive. The mean osmolarity value obtained here was 305, which is similar to values reported for normal subjects.39,41 To enhance repeatability and improve meniscus measurement and capture, in this study we combined digital video capture with software image analysis assistance, as in an earlier study.34 Through the use of capture techniques, images can be objectively and accurately interpreted, and detailed measurements can be made later. Here we used the ImageJ (National Institutes of Health)33 package to measure TMH in its central portion (at 6 o’clock) as the distance between the darker edge of the lower eyelid and the upper limit of the TM.19,21,22,27,28,34 According to our findings, we propose the use of TMH photographs to design a grading scale for clinical guidance. In effect, grading scales for anterior eye variables (e.g., bulbar redness) have significantly improved the monitoring of ocular physiology changes and are proving more stable and sensitive than verbal descriptions.58,59 Our results indicate better correlation between tear film variables in symptomatic patients and older subjects, whose tear film characteristics are worse than those in younger subjects.60 We observed that older persons obtained worse scores in the OSDI and McMonnies questionnaires (Table 3). In addition, older subjects showed worse dry eye symptoms (the mean age of subjects classed as having DED by the two questionnaires was 42.03 years, whereas those whose scores in neither or one questionnaire indicated DED were 20.81 and 25.93 years, respectively; Table 4). Our study also revealed that TM quality (both objective and subjective measurements) and osmolarity were better correlated in symptomatic subjects, especially those whose scores in both questionnaires indicated they had DED. Our findings also confirm the assumption made by Tomlinson et al.23 that the potential for correlation is greater with a wider range of values offered by the inclusion of a dry eye group and that normal subjects, however, may yield significance if a large enough range of parameter values is included. Moreover, it appears that the use of inexpensive questionnaires and subjective TM grading (as opposed to expensive osmolarity testing and video recording) may be a valid protocol for dry eye screening purposes, especially for older, more symptomatic subjects. To identify the etiology of the DED, however, several tests are needed including osmolarity measurement, because hyperosmolarity is known to play an important role in the pathogenesis of dry eye.
ACKNOWLEDGMENTS This study was funded by the Spanish Ministry of Science and Education and the Instituto de Salud Carlos III through research grant PI10/01098. The authors have no financial relationship with the organization sponsoring this research. Received August 10, 2013; accepted July 3, 2013.
REFERENCES FIGURE 8. Correlation between osmolarity and TM variables in subjects whose scores in two questionnaires indicated dry eye. (A) Correlation between osmolarity and TMH (Pearson test). (B) Correlation between osmolarity and subjective TM (Spearman Q test). (C) Correlation between TMH and subjective TM (Spearman Q test).
1. Julio G, Lluch S, Pujol P, Merindano MD. Effects of tear hyperosmolarity on conjunctival cells in mild to moderate dry eye. Ophthalmic Physiol Opt 2012;32:317Y23. 2. McGinnigle S, Naroo SA, Eperjesi F. Evaluation of dry eye. Surv Ophthalmol 2012;57:293Y316.
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1428 Tear Osmolarity and Tear MeniscusVGarcı´a-Resu´a et al. 3. Lemp MA, Bron AJ, Baudouin C, Benitez Del Castillo JM, Geffen D, Tauber J, Foulks GN, Pepose JS, Sullivan BD. Tear osmolarity in the diagnosis and management of dry eye disease. Am J Ophthalmol 2011;151:792Y8. 4. Lemp M, Baudouin C, Baum J, Dogru M, Foulks GN, Kinoshita S, Laibson P, McCulley J, Murube J, Pfugfelder SC, Rolando M, Toda I. The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007;5:75Y92. 5. Stahl U, Willcox M, Stapleton F. Osmolality and tear film dynamics. Clin Exp Optom 2012;95:3Y11. 6. Smith JA, Albeitz J, Begley C, Caffery B, Nichols K, Schaumberg D, Schein O. The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007;5:93Y107. 7. de Paiva CS, Lindsey JL, Pflugfelder SC. Assessing the severity of keratitis sicca with videokeratoscopic indices. Ophthalmology 2003;110:1102Y9. 8. Pflugfelder SC, Tseng SC, Sanabria O, Kell H, Garcia CG, Felix C, Feuer W, Reis BL. Evaluation of subjective assessments and objective diagnostic tests for diagnosing tear-film disorders known to cause ocular irritation. Cornea 1998;17:38Y56. 9. McMonnies CW, Ho A. Responses to a dry eye questionnaire from a normal population. J Am Optom Assoc 1987;58:588Y91. 10. Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and validity of the Ocular Surface Disease Index. Arch Ophthalmol 2000;118:615Y21. 11. Korb DR. Survey of preferred tests for diagnosis of the tear film and dry eye. Cornea 2000;19:483Y6. 12. Benelli U, Nardi M, Posarelli C, Albert TG. Tear osmolarity measurement using the TearLab Osmolarity System in the assessment of dry eye treatment effectiveness. Cont Lens Anterior Eye 2010; 33:61Y7. 13. Sullivan BD, Whitmer D, Nichols KK, Tomlinson A, Foulks GN, Geerling G, Pepose JS, Kosheleff V, Porreco A, Lemp MA. An objective approach to dry eye disease severity. Invest Ophthalmol Vis Sci 2010;51:6125Y30. 14. Bron AJ, Smith JA, Calonge M. Methodologies to diagnose and monitor dry eye disease: report of the Diagnostic Methodology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007;5:108Y52. 15. Holly FJ. Physical chemistry of the normal and disordered tear film. Trans Ophthalmol Soc U K 1985;104:374Y80. 16. Nichols KK, Nichols JJ, Zadnik K. Frequency of dry eye diagnostic test procedures used in various modes of ophthalmic practice. Cornea 2000;19:477Y82. 17. Lim KJ, Lee JH. Measurement of the tear meniscus height using 0.25% fluorescein sodium. Korean J Ophthalmol 1991;5:34Y6. 18. Guillon JP, Guillon M. The role of tears in contact lens performance and its measurement. In: Ruben M, Guillon M, eds. Contact Lens Practice. London, UK: Chapman & Hall; 1994:453Y83. 19. Garcia-Resua C, Santodomingo-Rubido J, Lira M, Giraldez MJ, Vilar EY. Clinical assessment of the lower tear meniscus height. Ophthalmic Physiol Opt 2009;29:487Y96. 20. Mainstone JC, Bruce AS, Golding TR. Tear meniscus measurement in the diagnosis of dry eye. Curr Eye Res 1996;15:653Y61. 21. Santodomingo-Rubido J, Wolffsohn JS, Gilmartin B. Comparison between graticule and image capture assessment of lower tear film meniscus height. Cont Lens Anterior Eye 2006;29:169Y73.
22. Johnson ME, Murphy PJ. The agreement and repeatability of tear meniscus height measurement methods. Optom Vis Sci 2005; 82:1030Y7. 23. Tomlinson A, Blades KJ, Pearce EI. What does the phenol red thread test actually measure? Optom Vis Sci 2001;78:142Y6. 24. Lamberts DW, Foster CS, Perry HD. Schirmer test after topical anesthesia and the tear meniscus height in normal eyes. Arch Ophthalmol 1979;97: 1082Y5. 25. Miller WL, Doughty MJ, Narayanan S, Leach NE, Tran A, Gaume AL, Bergmanson JP. A comparison of tear volume (by tear meniscus height and phenol red thread test) and tear fluid osmolality measures in non-lens wearers and in contact lens wearers. Eye Contact Lens 2004;30:132Y7. 26. Oguz H, Yokoi N, Kinoshita S. The height and radius of the tear meniscus and methods for examining these parameters. Cornea 2000;19:497Y500. 27. Patel S, Wallace I. Tear meniscus height, lower punctum lacrimale, and the tear lipid layer in normal aging. Optom Vis Sci 2006; 83:731Y9. 28. Kwong YM, Cho P. Tear meniscus height in normal and dry eyes: evaluation using the Topcon IMAGEnet System. Optom Today 2001;4124:28Y31. 29. Doughty MJ, Laiquzzaman M, Oblak E, Button N. The tear (lacrimal) meniscus height in human eyes: a useful clinical measure or an unusable variable sign? Cont Lens Anterior Eye 2002;25:57Y65. 30. Port MJA, Asaria TS. The assessment of human tear flow. J Br Contact Lens Assoc 1990;13:76Y82. 31. Pult H, Riede-Pult B. Comparison of subjective grading and objective assessment in meibography. Cont Lens Anterior Eye 2013;36:22Y7. 32. Srinivasan S, Menzies K, Sorbara L, Jones L. Infrared imaging of meibomian gland structure using a novel keratograph. Optom Vis Sci 2012;89:788Y94. 33. Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods 2012;9:671Y5. 34. Garcı´a-Resu´a C, Pena-Verdeal H, Lira M, Real Oliveira ME, Giraldez MJ, Yebra-Pimentel E. Comparison between three methods to value lower tear meniscus measured by image software. In: Filipe M, Martins-Costa PC, eds. 8th Iberoamerican Optics Meeting and 11th Latin American Meeting on Optics, Lasers, and Applications. Porto, Portugal: SPIE; 2013. 35. Korb DR. The tear filmVits role today and in the future. In: Korb D, Craig J, Doughty M, Guillon JP, Tomlinson A, Smith G, eds. The Tear Film: Structure, Function and Clinical Examination. Boston, MA: Butterworth-Heinemann; 2002:126Y92. 36. Khurana AK, Chaudhary R, Ahluwalia BK, Gupta S. Tear film profile in dry eye. Acta Ophthalmol (Copenh) 1991;69:79Y86. 37. Farris RL, Stuchell RN, Nisengard R. Sjogren’s syndrome and keratoconjunctivitis sicca. Cornea 1991;10:207Y9. 38. Farris RL, Gilbard JP, Stuchell RN, Mandel ID. Diagnostic tests in keratoconjunctivitis sicca. CLAO J 1983;9:23Y8. 39. Tomlinson A, Khanal S, Ramaesh K, Diaper C, McFadyen A. Tear film osmolarity: determination of a referent for dry eye diagnosis. Invest Ophthalmol Vis Sci 2006;47:4309Y15. 40. Messmer EM, Bulgen M, Kampik A. Hyperosmolarity of the tear film in dry eye syndrome. Dev Ophthalmol 2010;45:129Y38. 41. Tomlinson A, McCann LC, Pearce EI. Comparison of human tear film osmolarity measured by electrical impedance and freezing point depression techniques. Cornea 2010;29:1036Y41. 42. Lemp MA. Report of the National Eye Institute/Industry workshop on Clinical Trials in Dry Eyes. CLAO J 1995;21:221Y32.
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Copyright © American Academy of Optometry. Unauthorized reproduction of this article is prohibited.
Tear Osmolarity and Tear MeniscusVGarcı´a-Resu´a et al. 43. Yildiz EH, Fan VC, Banday H, Ramanathan LV, Bitra RK, Garry E, Asbell PA. Evaluation of a new tear osmometer for repeatability and accuracy, using 0.5-microL (500-Nanoliter) samples. Cornea 2009;28:677Y80. 44. Versura P, Profazio V, Campos EC. Performance of tear osmolarity compared to previous diagnostic tests for dry eye diseases. Curr Eye Res 2010;35:553Y64. 45. Moore JE, Graham JE, Goodall EA, Dartt DA, Leccisotti A, McGilligan VE, Moore TC. Concordance between common dry eye diagnostic tests. Br J Ophthalmol 2009;93:66Y72. 46. Nichols KK, Nichols JJ, Mitchell GL. The lack of association between signs and symptoms in patients with dry eye disease. Cornea 2004;23:762Y70. 47. Ray WA, O’Day DM. Statistical analysis of multi-eye data in ophthalmic research. Invest Ophthalmol Vis Sci 1985;26:1186Y8. 48. Patel VD, Watanabe JH, Strauss JA, Dubey AT. Work productivity loss in patients with dry eye disease: an online survey. Curr Med Res Opin 2011;27:1041Y8. 49. McMonnies C, Ho A, Wakefield D. Optimum dry eye classification using questionnaire responses. Adv Exp Med Biol 1998;438:835Y8. 50. Glasson MJ, Stapleton F, Keay L, Sweeney D, Willcox MD. Differences in clinical parameters and tear film of tolerant and intolerant contact lens wearers. Invest Ophthalmol Vis Sci 2003;44:5116Y24. 51. Miller KL, Walt JG, Mink DR, Satram-Hoang S, Wilson SE, Perry HD, Asbell PA, Pflugfelder SC. Minimal clinically important difference for the ocular surface disease index. Arch Ophthalmol 2010;128:94Y101. 52. McMonnies CW. Key questions in a dry eye history. J Am Optom Assoc 1986;57:512Y7.
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53. Ogasawara K, Mitsubayashi K, Tsuru T, Karube I. Electrical conductivity of tear fluid in healthy persons and keratoconjunctivitis sicca patients measured by a flexible conductimetric sensor. Graefes Arch Clin Exp Ophthalmol 1996;234:542Y6. 54. Dunn G. Design and Analysis of Reliability Studies: The Statistical Evaluation of Measurement Errors. Oxford, NY: Oxford University Press; 1989. 55. Gilbard JP, Farris RL, Santamaria J, 2nd. Osmolarity of tear microvolumes in keratoconjunctivitis sicca. Arch Ophthalmol 1978;96:677Y81. 56. Yokoi N, Komuro A. Non-invasive methods of assessing the tear film. Exp Eye Res 2004;78: 399Y407. 57. Cermak JM, Krenzer KL, Sullivan RM, Dana MR, Sullivan DA. Is complete androgen insensitivity syndrome associated with alterations in the meibomian gland and ocular surface? Cornea 2003; 22:516Y21. 58. Schulze MM, Hutchings N, Simpson TL. The perceived bulbar redness of clinical grading scales. Optom Vis Sci 2009;86:1250Y8. 59. Peterson RC, Wolffsohn JS. Objective grading of the anterior eye. Optom Vis Sci 2009;86:273Y8. 60. Ozdemir M, Temizdemir H. Age- and gender-related tear function changes in normal population. Eye (Lond) 2010;24:79Y83.
Carlos Garcı´a-Resu´a ´ ptica y Optometrı´a Facultad de O Campus Vida Universidad de Santiago de Compostela 15782 Santiago de Compostela Galicia, Spain e-mail: [email protected]
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ORIGINAL ARTICLE
Correlation between Tear Osmolarity and Tear Meniscus Carlos Garcı´a-Resu´a*, Hugo Pena-Verdeal*, Beatriz Remeseiro†, Maria J. Gira´ldez†, and Eva Yebra-Pimentel‡
ABSTRACT Purpose. To examine the relationship between tear meniscus height (TMH) and subjective meniscus grading (subjective tear meniscus [TM]) with tear osmolarity. Methods. Tear osmolarity measurements (using TearLab) and digital images of the TM were obtained in 177 consecutive patients undergoing an eye examination at our optometry clinic (Universidad de Santiago de Compostela, Spain) who fulfilled the study’s inclusion criteria. Participants were also administered the McMonnies and Ocular Surface Disease Index questionnaires for the detection of dry eye disease. The lower TM was videotaped by a digital camera attached to a slit lamp in its central portion without fluorescein instillation. After the study, a masked observer extracted an image from each video and measured the TMH using open source software (NIH ImageJ). Subsequently, the masked observer subjectively graded the appearance of each meniscus. For statistical analysis, subjects were stratified by age and by dry eye symptoms as indicated by their scores in the two questionnaires. Results. In the whole study population, a significant relationship was observed between osmolarity and TMH (r = j0.41, p G 0.001) and osmolarity and subjective TM (r = 0.35, p G 0.001). A cluster analysis revealed similar correlations when subjects were stratified by age or dry eye symptoms, these correlations being more pronounced in older and more symptomatic subjects. Objective TMH measurements and subjective meniscus quality were also correlated (r = j0.75, p G 0.001). Conclusions. Osmolarity and both objective TMH measurements and subjective interpretation of the meniscus showed high correlation, especially in older symptomatic subjects. (Optom Vis Sci 2014;91:1419Y1429) Key Words: osmolarity, tear meniscus, TearLab osmometer, ImageJ software
D
ry eye disease (DED) is a common condition that causes discomfort and visual distortions. The characteristic features of DED are changes in tear film composition and inflammation of the ocular surface.1Y4 An abnormally high tear film osmolarity induces inflammatory events that negatively affect ocular surface cells,1Y5 leading to symptoms such as eye irritation and blurred vision with impacts on quality of life.4,6Y8 Dry eye disease is also the main reason why subjects stop wearing contact lenses.6 There are a variety of diagnostic tools available for DED. Most methods are based on assessing symptoms and include *OD, MSc † OD, MSc, PhD ‡ OD, PhD Department of Applied Physics (Optometry Group GI-2092), University of Santiago de Compostela, Santiago de Compostela, Spain (CG-R, HP-V, MJG, EY-P); and Departamento de Computacio´n, Universidade da Coruna, Campus de Elvin˜a s/n, A Corun˜a, Spain (BR).
questionnaires like the McMonnies or the Ocular Surface Disease Index (OSDI), which have been adapted for the detection of DED.9,10 Other tests commonly used are the Schirmer test, tear film break-up time, meibomian secretion scoring, and sodium fluorescein and lissamine green staining of the cornea and conjunctiva.11Y13 However, many of these tests are invasive or require eye manipulation, which could destabilize the tear film.14 The method proposed here, measuring tear meniscus height (TMH), provides a noninvasive indication of the total volume of the tear film.15 Tear meniscus height is routinely measured by eye care practitioners through slit-lamp biomicroscopy.11,16 Reported mean TMH values for healthy eyes range from 0.14 to 0.46 mm,17Y30 depending on the technique used17,21Y25 and the different end points used.19Y22,26Y30 The most widely used method involves image capture of the meniscus using a camera attached to a slit lamp, and TMH measurements may be quantified by software assistance.31,32 ImageJ33 is a free domain image analysis tool that
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1420 Tear Osmolarity and Tear MeniscusVGarcı´a-Resu´a et al. TABLE 1.
Subjective classification of the meniscus scheme Grade
Group
Description
1
Intact
2 3
Slightly diminished Markedly diminished or discontinuous
4
Absent
Meniscus of variable height and regular shape. Absence of debris Regular, but less visible. Absence of debris Diminished meniscus of irregular shape. Presence of debris Invisible meniscus
quantifies features viewed in a picture.34 This software helps interpret TMH data by enhancing resolution and hence the repeatability of measurements.34 In routine clinical practice, TMH is often measured using a graticule eyepiece attached to a biomicroscope.19,21,24,25,27 However, using this method, it is difficult to distinguish the upper limit of the tear meniscus (TM) during eye movement.29 This has determined that many clinicians prefer subjective assessment of the TM appearance, or TM quality, over TMH measurements.35 The main factors determined during TM assessment are the presence/absence of debris and/or foaming, its regularity (whether the top forms a regular or irregular line), and an estimate of height36,37 (Table 1). Tear fluid hyperosmolarity is a common feature to all types of DED. Normal tear film osmolarity is 302 T 6.3 mOsm/l,38Y40 whereas a mean of 321 mOsm/l is reported for DED.39 The most commonly used cutoff for a diagnosis of DED is 316 mOsm/l,39,41 which provides a sensitivity of 73% and a specificity of 90%.41
Grades 1 and 2 represent healthy meniscus Grades 3 and 4 represent abnormal meniscus
Hyperosmolarity has been described by the Tear Film and Ocular Surface Society Dry Eye Workshop as one of the main mechanisms of DED,4 being the main cause of discomfort, ocular surface damage, and inflammation.1,3,38,42 This has meant that tear film osmolarity measurement is considered the gold standard for DED diagnosis.2,4Y6,40,43,44 One of the main dilemmas when trying to make a diagnosis of DED is the poor correlation between dry eye tests,23,45 along with a lack of correlation between symptoms and objective signs.46 Osmolarity is defined as the number of dissolved solute particles in 1 kg of solution, regardless of particle shape, size, density, configuration, or charge.5 Hence, a higher osmolarity will induce a greater amount of evaporation from the eye surface and thus reduce tear film volume. Given the TM holds some 75 to 90% of the total tear film volume,15 any reduction in TMH should indicate an increase in tear film osmolarity. This study was designed to examine the relationship between TMH and osmolarity using the TearLab electric impedance osmometer to
FIGURE 1. Example of how TMH is measured by the ImageJ software. A color version of this figure is available online at www.optvissci.com. Optometry and Vision Science, Vol. 91, No. 12, December 2014
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TABLE 2.
Descriptive statistics
McMonnies OSDI Osmolarity TMH Subjective TM
Mean/ median
SD/IQR
Minimum
Maximum
6.00 8.33 305.68 0.20 1.00
3.00Y13.00 4.17Y17.71 14.37 0.06 1.00Y2.00
0.00 0.00 275.00 0.06 1.00
33.00 64.58 357.00 0.36 4.00
DED questionaires (McMonnies and OSDI) and subjective TM are dimensionless parameters. Osmolarity is indicated in milliosmoles per liter and TMH is indicated in millimeters. Mean and SD for parametric variables; median and interquartile range (IQR) for nonparametric variables. n = 177.
determine osmolarity and a new software tool to measure TMH. Subjective interpretation of TM appearance was also compared with objective TMH and osmolarity determinations. In addition, a cluster analysis was performed to examine the effects on the correlations observed of age and of symptoms expressed as the scores obtained in two dry eye grading questionnaires (OSDI and McMonnies).
METHODS Subjects and Procedures One hundred seventy-seven consecutive patients (78 male, 99 female) with a mean (TSD) age of 25.92 (T12.03) years (range, 18 to 65 years) were recruited among subjects visiting the Optometry Clinic of the Optometry Faculty (Universidad de Santiago de Compostela, Spain) for an eye examination. Subjects were excluded if they had a history of conjunctival, scleral, or corneal disease; prior eye surgery; glaucoma; diabetes mellitus; or a thyroid disorder or wore contact lenses. Qualifying subjects were administered two DED questionnaires (OSDI and McMonnies) and scheduled for another visit for tear osmolarity and meniscus height measurements. No participant was under any type of medication or used artificial tears at the time of the testing session. The study protocol adhered to the tenets of the Declaration of Helsinki and was approved by the Ethics Committee of the University of Santiago de Compostela (Spain). Only the right eye was examined because of induced excess tearing in the second eye and to avoid overstating the precision of statistical estimates.47 All measurements were performed between 5 PM and 6 PM. Throughout the study, laboratory conditions of temperature, light, and humidity were kept constant (temperature, 20 to 23-C; relative humidity, 50 to 60%).
DED Questionnaires The questionnaires at the screening visit were OSDI6,10,48 and McMonnies grading DED questionnaires,6,9,49,50 which established the symptoms statement of the patient.
Ocular Surface Disease Index The OSDI (Allergan Inc, Irvine, CA)51 is a 12-item selfadministered questionnaire designed for rapid assessment of ocular surface symptoms related to chronic DED, severity, and their effects on the patient. Total OSDI scores were calculated
FIGURE 2. Correlation between osmolarity and TM variables in the whole study population. (A) Correlation between osmolarity and TMH (Pearson test). (B) Correlation between osmolarity and subjective TM (Spearman Q test). (C) Correlation between TMH and subjective TM (Spearman Q test).
Optometry and Vision Science, Vol. 91, No. 12, December 2014
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1422 Tear Osmolarity and Tear MeniscusVGarcı´a-Resu´a et al. TABLE 3.
Descriptive statistics for the age rangeYstratified groups e20 y (n = 88) Age range Age McMonnies OSDI Osmolarity TMH Subjective TM
Q45 y (n = 22)
Between 20 and 45 y (n = 67)
Mean/median
SD/IQR
Mean/median
SD/IQR
Mean/median
SD/IQR
18.93 4.50 8.33 303.93 0.21 1.00
0.85 3.00Y7.00 4.17Y12.50 15.76 0.05 1.00 Y 2.00
30.83 6.00 10.42 304.80 0.20 1.00
6.39 4.00Y12.00 4.17Y18.75 12.01 0.051 1.00Y2.00
54.18 20.00 31.25 315.41 0.18 2.00
6.27 15.00Y27.25 16.66Y43.23 11.55 0.08 1.00Y3.00
DED questionaires (McMonnies and OSDI) and subjective TM are dimensionless parameters. Age is indicated in years, osmolarity is indicated in milliosmoles per liter, and TMH is indicated in millimeters. Mean and SD for parametric variables; median and interquartile range (IQR) for nonparametric variables.
according to published guidelines,10,51 and a score of 13 or more was established as the cutoff for DED.6,10,48
OSDI ¼
Sum of Scores 25 Number of Questions Answered
McMonnies Subjects completed a modified McMonnies dry eye questionnaire to assess dryness symptom number, type, and frequency.52 This 12-item questionnaire elicits information about recent medical and medication history that could affect tear production. Symptoms included in the questionnaire are eye soreness, scratchiness, dryness, and grittiness (from the original McMonnies questionnaire) along with burning, stinging, foreign body sensation, and itchiness. As in prior studies, a cutoff of 14.549,50 was used to differentiate between normality and mild to severe DED.
Tear Meniscus Height Video Capture and Image Selection Meniscus videos were recorded by a Topcon DV-3 digital camera attached to the slit lamp and stored using Topcon IMAGEnet i-base at a spatial resolution of 1024 768 pixels in the RGB color space. Subjects seated at the slit lamp were instructed to look at a target positioned to induce primary eye gaze and a natural blink. The TM was acquired centrally (at the 6-o’clock position) (Fig. 1) with magnification set at 500 (objective 40, ocular 12.5; without fluorescein). To avoid reflex tearing, a short moderate-illumination light beam (3 mm wide, 5 mm height) was used to prevent the light shining directly into the pupil during measurements.19 In total, 177 TM images extracted from recorded videos were examined. Images were selected from the recordings at the point when a fully expanded stable meniscus was observed after the blink. A blinded observer then measured TMH by computerassisted image analysis and outgrowth size was quantified using ImageJ software v1.47i (National Institutes of Health, Bethesda, MD; http://imagej.nih.gov/ij/).33 Subsequent to TMH measurement, the observer assigned a subjective classification category to each central meniscus.
Objective Measurement of TMH The TM was measured according to defined criteria19,34 in its central portion (at 6 o’clock) as the distance between the darker
edge of the lower eyelid and the upper limit of the TM using ImageJ. The TMH was marked using the straight tool, which allows the user to draw a line (Fig. 1) in the middle of the illuminated area perpendicular to the eyelid margin, from the lowest meniscus limit to the highest one. Next, the height of the TM was calculated according to the software pixels, which were transformed into millimeters as 300 pixels = 1 mm. This conversion factor was previously calculated for our camera.
Subjective Meniscus Grading The appearance of the meniscus was also graded according to the criteria described in Table 1, whereby grades 1 and 2 indicate a healthy or control meniscus and grades 3 and 4 represent an abnormal meniscus. The grading scale was based on that published by Khurana et al.36 and later modified by Garcia-Resua et al.19 This evaluation was performed on the image obtained for the central TM using the slit lamp (Fig. 1).
Osmolarity: TearLab Osmometer The TearLab Osmometer (TearLab Corp, San Diego, CA) was used to measure the osmolarity of the tear film.5,53 The subject was seated with the chin tilted upward and eyes directed toward the ceiling. The instrument probe (housing the disposable microchip) is then placed on the lower TM until a beep is emitted, indicating that the tear sample has been collected. Only a 0.05-Kl tear sample is needed and measurements are directly made on the TM using the probe, which takes up the sample through capillary action.2,12,13 The TearLab quickly (in less than 10 seconds) converts the electrical impedance of the sample into osmolarity in milliosmoles per liter, which is displayed on the device screen. Its measurement range is 275 to 400 mOsm/l.
Statistical Analysis After confirming their normal distribution using the KolmogorovSmirnov test, numerical data (osmolarity and TMH) were compared using parametric tests. Nonparametric tests were used for McMonnies scores, OSDI scores, and subjective TM grades. Numerical variables are provided as means and their SD, whereas nonparametric variables are expressed as medians and interquartile ranges.
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Tear Osmolarity and Tear MeniscusVGarcı´a-Resu´a et al.
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FIGURE 3.
FIGURE 4.
Correlation between osmolarity and TM variables in subjects aged 20 years or younger. (A) Correlation between osmolarity and TMH (Pearson test). (B) Correlation between osmolarity and subjective TM (Spearman Q test). (C) Correlation between TMH and subjective TM (Spearman Q test).
Correlation between osmolarity and TM variables in subjects aged 20 to 45 years. (A) Correlation between osmolarity and TMH (Pearson test). (B) Correlation between osmolarity and subjective TM (Spearman Q test). (C) Correlation between TMH and subjective TM (Spearman Q test).
Optometry and Vision Science, Vol. 91, No. 12, December 2014
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1424 Tear Osmolarity and Tear MeniscusVGarcı´a-Resu´a et al.
To examine the effects of age and DED symptoms on correlations between variables, a cluster analysis was also performed on three data sets: & Whole study population: 177 subjects (N = 177). & Subjects stratified by age: 25 years or younger (n = 88), 25 to 45 years (n = 67), and 45 years or older (n = 22). & Subjects stratified by symptoms: a score indicating DED in both questionnaires (n = 104), a score indicating DED in one questionnaire (n = 40), and a score indicating the absence of DED in both questionnaires (n = 33). Relationships were assessed through Pearson correlation for parametric data and through Spearman Q for nonparametric data. Correlations between variables were described as weak (0.2 to 0.4), moderate (0.4 to 0.6), fairly good (0.61 to 0.8), or strong (0.8 to 1.0).50,54 All statistical tests were performed using the software package SPSS v. 19.0 for Windows (SPSS Inc, Chicago, IL). Significance was set at p e 0.05.
RESULTS Whole Study Population Descriptive statistics for the whole study population (N = 177) are provided in Table 2. In our subjective TM evaluation, most subjects showed an intact (n = 109) or slightly diminished (n = 45) meniscus. An abnormal TM was detected in 29 subjects in whom the meniscus was described as markedly diminished or discontinuous and in 2 subjects lacking a meniscus. Fig. 2 shows the correlation between osmolarity and both the objective and subjective TM data recorded for the study group. Osmolarity was moderately negatively correlated with TMH (r = j0.41, p G 0.001) and weakly positively correlated with subjective TM quality (r = 0.35, p G 0.001). As expected, strong negative correlation was observed between TMH and TM quality (r = j0.75, p G 0.001), indicating that the worse the subjective meniscus quality, the smaller the objective TMH measurement.
Stratification by Age
FIGURE 5. Correlation between osmolarity and TM variables in subjects aged 45 years or older. (A) Correlation between osmolarity and TMH (Pearson test). (B) Correlation between osmolarity and subjective TM (Spearman Q test). (C) Correlation between TMH and subjective TM (Spearman Q test).
Descriptive statistics for the subjects stratified into three age groups are provided in Table 3. As for the whole study population, osmolarity was correlated with both subjective meniscus quality and objective TMH for each age range. In all age groups, osmolarity was inversely related to TMH, and correlation was greater with age. Thus, correlation was weak for the younger subject group (r = j0.28, p = 0.01) (Fig. 3A) and moderate for the older groups (G45 years, r = j0.40, p = 0.001, and 945 years, r = j0.52, p = 0.014; Figs. 4A and 5A). Correlation between osmolarity and TM quality was weak to fairly good depending on age (from r = 0.27 for e20 years to r = 0.63 for Q45 years, all p G 0.012) (Figs. 3B, 4B, and 5C). When examining TMH and TM quality, significant correlation was observed (p G 0.001 in all cases) ranging from fairly good (r = j0.69 for subjects aged e20 years to r = j0.75 for subjects aged 20 to 45 years) (Figs. 3C and 4C) to strong (r = j0.90 for subjects aged Q45 years)
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Tear Osmolarity and Tear MeniscusVGarcı´a-Resu´a et al.
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TABLE 4.
Descriptive statistics for the symptom assessmentYstratified groups Fail no questionnaire (n = 104) Age McMonnies OSDI Osmolarity TMH Subjective TM
Fail one questionnaire (n = 40)
Fail two questionnaires (n = 33)
Mean/median
SD/IQR
Mean/median
SD/IQR
Mean/median
SD/IQR
20.81 4.00 6.25 302.26 0.21 1.00
3.64 3.00Y6.00 2.08Y8.33 14.17 0.05 1.00Y2.00
25.93 10.00 16.67 308.60 0.20 2.00
12.60 6.00Y13.00 14.58Y22.92 14.75 0.06 1.00Y2.00
42.03 17.00 29.17 312.92 0.15 2.00
14.37 15.00Y25.50 19.79Y40.63 11.04 0.07 1.00Y3.00
DED questionaires (McMonnies and OSDI) and subjective TM are dimensionless parameters. Age is indicated in years, osmolarity is indicated in milliosmoles per liter, and TMH is indicated in millimeters. Mean and SD for parametric variables; median and interquartile range (IQR) for nonparametric variables.
(Fig. 5C) such that greater objective and subjective TM data were better correlated in older subjects.
Stratification by Symptoms Descriptive statistics for the subjects stratified according to their questionnaire scores are provided in Table 4. Figs. 6 to 8 illustrate correlations among the variables examined detected in each of the three symptom groups. Once again, TMH versus osmolarity and TMH versus TM quality were negatively correlated, whereas positive correlation was detected between osmolarity and TM quality. For nonsymptomatic subjects (scores in both questionnaires indicated no DED), correlation between osmolarity and meniscus variables was very weak for both the objective (TMH) (r = j0.19, p = 0.049) (Fig. 6A) and subjective (TM quality) (r = 0.08, p = 0.4) (Fig. 6B) assessments. In subjects with mild symptoms (scores in one questionnaire indicated DED), this relationship was moderate in both comparisons (r = j0.48, p = 0.002 for osmolarity vs. TMH; r = 0.51, p G 0.001 for osmolarity vs. TM quality) (Fig. 7A, B). Finally, when only strongly symptomatic subjects were considered (scores in both questionnaires indicated DED), osmolarity correlations with both the objective (r = j0.52, p = 0.002, for osmolarity vs. TMH, Fig. 8A) and subjective (r = 0.64, p G 0.001 for osmolarity vs. TM quality, Fig. 8B) meniscus variables were slightly improved over those observed in the subjects with mild DED symptoms. Correlations between objective TMH and subjective TM quality measurements were fairly good in nonsymptomatic subjects (r = j0.60, p G 0.001) (Fig. 6C) and strong in those with mild or severe symptoms (r = j0.81, p G 0.001 or r = j0.90, p G 0.001, respectively; Figs. 7C and 8C). Thus, correlations became stronger with increasing symptoms.
DISCUSSION In this study, we detected an expected statistically significant relationship between osmolarity and TMH (Fig. 2) such that higher osmolarity values (indicating poorer tear film quality) give rise to lower TMH values. This trend was also observed in the cluster analysis (Figs. 3 to 8), whereby osmolarity and TMH showed improved correlation when one questionnaire indicated DED and even better correlation when both questionnaires
identified dry eye symptoms. This suggests that correlations between these tear film tests are more pronounced in symptomatic subjects. In addition, when the study population was stratified by age, better correlation between the two variables was noted in the older subjects. In agreement with this finding, Glasson et al.50 detected a lower TMH in symptomatic intolerant contact lens wearers than control subjects. These authors also noted that TMH correlated negatively with osmolarity (Pearson correlation for meniscus height [mm] vs. osmolarity [mOsm/kg] was r = j0.566, p = 0.014 and r = j0.438, p = 0.047 for two subject groups).50 On the contrary, Nichols et al.46 detected no correlation between TMH and symptoms of dry eye. However, TMH was measured using the variable beam height on the slit-lamp biomicroscope, which is a less precise method and much more influenced by subjective errors and interpretation than the image analysis method used here. Several authors have related higher osmolarity values to tear film abnormalities, which lead to symptoms and discomfort.14,38Y40,55 Moreover, a lower TMH appears to induce similar symptoms in patients with different forms of DED20,56,57; thus, we would expect higher osmolarity values in subjects with lower meniscus heights. When the TM was subjectively graded, significant correlation was also found between a higher osmolarity and worse meniscus quality. This relationship was significant and gained in strength as subject age and dry eye symptoms increased. Finally, when we compared objective TMH measurements with subjective interpretations of meniscus quality, good to strong correlation was observed between subjective meniscus assessment and TMH (Figs. 2 to 8). This determined that for lower TMH values measured using software assistance, an experienced observer graded the TM as worse, and again stronger correlation was shown in older and more symptomatic subjects. This finding is consistent with the results of a previous study in which we measured TMH using a graticule eyepiece.19 Accordingly, based on objective TMH measurements, a meniscus picture scale could be designed to help clinicians grade the TM. Few studies have addressed the relationship between osmolarity and TMH,25 and even fewer have considered the subjective interpretation of the TM. Using the TearLab osmometer, tear osmolarity can be easily and quickly measured. However, the method has two important shortcomings: methods based on the electric impedance principle are less repeatable than freezing pointYbased techniques,41 and
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1426 Tear Osmolarity and Tear MeniscusVGarcı´a-Resu´a et al.
FIGURE 6.
FIGURE 7.
Correlation between osmolarity and TM variables in subjects whose scores in two questionnaires indicated the absence of dry eye. (A) Correlation between osmolarity and TMH (Pearson test). (B) Correlation between osmolarity and subjective TM (Spearman Q test). (C) Correlation between TMH and subjective TM (Spearman Q test).
Correlation between osmolarity and TM variables in subjects whose scores in one questionnaire indicated dry eye. (A) Correlation between osmolarity and TMH (Pearson test). (B) Correlation between osmolarity and subjective TM (Spearman Q test). (C) Correlation between TMH and subjective TM (Spearman Q test).
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Tear Osmolarity and Tear MeniscusVGarcı´a-Resu´a et al.
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each TearLab measurement is quite expensive. The mean osmolarity value obtained here was 305, which is similar to values reported for normal subjects.39,41 To enhance repeatability and improve meniscus measurement and capture, in this study we combined digital video capture with software image analysis assistance, as in an earlier study.34 Through the use of capture techniques, images can be objectively and accurately interpreted, and detailed measurements can be made later. Here we used the ImageJ (National Institutes of Health)33 package to measure TMH in its central portion (at 6 o’clock) as the distance between the darker edge of the lower eyelid and the upper limit of the TM.19,21,22,27,28,34 According to our findings, we propose the use of TMH photographs to design a grading scale for clinical guidance. In effect, grading scales for anterior eye variables (e.g., bulbar redness) have significantly improved the monitoring of ocular physiology changes and are proving more stable and sensitive than verbal descriptions.58,59 Our results indicate better correlation between tear film variables in symptomatic patients and older subjects, whose tear film characteristics are worse than those in younger subjects.60 We observed that older persons obtained worse scores in the OSDI and McMonnies questionnaires (Table 3). In addition, older subjects showed worse dry eye symptoms (the mean age of subjects classed as having DED by the two questionnaires was 42.03 years, whereas those whose scores in neither or one questionnaire indicated DED were 20.81 and 25.93 years, respectively; Table 4). Our study also revealed that TM quality (both objective and subjective measurements) and osmolarity were better correlated in symptomatic subjects, especially those whose scores in both questionnaires indicated they had DED. Our findings also confirm the assumption made by Tomlinson et al.23 that the potential for correlation is greater with a wider range of values offered by the inclusion of a dry eye group and that normal subjects, however, may yield significance if a large enough range of parameter values is included. Moreover, it appears that the use of inexpensive questionnaires and subjective TM grading (as opposed to expensive osmolarity testing and video recording) may be a valid protocol for dry eye screening purposes, especially for older, more symptomatic subjects. To identify the etiology of the DED, however, several tests are needed including osmolarity measurement, because hyperosmolarity is known to play an important role in the pathogenesis of dry eye.
ACKNOWLEDGMENTS This study was funded by the Spanish Ministry of Science and Education and the Instituto de Salud Carlos III through research grant PI10/01098. The authors have no financial relationship with the organization sponsoring this research. Received August 10, 2013; accepted July 3, 2013.
REFERENCES FIGURE 8. Correlation between osmolarity and TM variables in subjects whose scores in two questionnaires indicated dry eye. (A) Correlation between osmolarity and TMH (Pearson test). (B) Correlation between osmolarity and subjective TM (Spearman Q test). (C) Correlation between TMH and subjective TM (Spearman Q test).
1. Julio G, Lluch S, Pujol P, Merindano MD. Effects of tear hyperosmolarity on conjunctival cells in mild to moderate dry eye. Ophthalmic Physiol Opt 2012;32:317Y23. 2. McGinnigle S, Naroo SA, Eperjesi F. Evaluation of dry eye. Surv Ophthalmol 2012;57:293Y316.
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1428 Tear Osmolarity and Tear MeniscusVGarcı´a-Resu´a et al. 3. Lemp MA, Bron AJ, Baudouin C, Benitez Del Castillo JM, Geffen D, Tauber J, Foulks GN, Pepose JS, Sullivan BD. Tear osmolarity in the diagnosis and management of dry eye disease. Am J Ophthalmol 2011;151:792Y8. 4. Lemp M, Baudouin C, Baum J, Dogru M, Foulks GN, Kinoshita S, Laibson P, McCulley J, Murube J, Pfugfelder SC, Rolando M, Toda I. The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007;5:75Y92. 5. Stahl U, Willcox M, Stapleton F. Osmolality and tear film dynamics. Clin Exp Optom 2012;95:3Y11. 6. Smith JA, Albeitz J, Begley C, Caffery B, Nichols K, Schaumberg D, Schein O. The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007;5:93Y107. 7. de Paiva CS, Lindsey JL, Pflugfelder SC. Assessing the severity of keratitis sicca with videokeratoscopic indices. Ophthalmology 2003;110:1102Y9. 8. Pflugfelder SC, Tseng SC, Sanabria O, Kell H, Garcia CG, Felix C, Feuer W, Reis BL. Evaluation of subjective assessments and objective diagnostic tests for diagnosing tear-film disorders known to cause ocular irritation. Cornea 1998;17:38Y56. 9. McMonnies CW, Ho A. Responses to a dry eye questionnaire from a normal population. J Am Optom Assoc 1987;58:588Y91. 10. Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and validity of the Ocular Surface Disease Index. Arch Ophthalmol 2000;118:615Y21. 11. Korb DR. Survey of preferred tests for diagnosis of the tear film and dry eye. Cornea 2000;19:483Y6. 12. Benelli U, Nardi M, Posarelli C, Albert TG. Tear osmolarity measurement using the TearLab Osmolarity System in the assessment of dry eye treatment effectiveness. Cont Lens Anterior Eye 2010; 33:61Y7. 13. Sullivan BD, Whitmer D, Nichols KK, Tomlinson A, Foulks GN, Geerling G, Pepose JS, Kosheleff V, Porreco A, Lemp MA. An objective approach to dry eye disease severity. Invest Ophthalmol Vis Sci 2010;51:6125Y30. 14. Bron AJ, Smith JA, Calonge M. Methodologies to diagnose and monitor dry eye disease: report of the Diagnostic Methodology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007;5:108Y52. 15. Holly FJ. Physical chemistry of the normal and disordered tear film. Trans Ophthalmol Soc U K 1985;104:374Y80. 16. Nichols KK, Nichols JJ, Zadnik K. Frequency of dry eye diagnostic test procedures used in various modes of ophthalmic practice. Cornea 2000;19:477Y82. 17. Lim KJ, Lee JH. Measurement of the tear meniscus height using 0.25% fluorescein sodium. Korean J Ophthalmol 1991;5:34Y6. 18. Guillon JP, Guillon M. The role of tears in contact lens performance and its measurement. In: Ruben M, Guillon M, eds. Contact Lens Practice. London, UK: Chapman & Hall; 1994:453Y83. 19. Garcia-Resua C, Santodomingo-Rubido J, Lira M, Giraldez MJ, Vilar EY. Clinical assessment of the lower tear meniscus height. Ophthalmic Physiol Opt 2009;29:487Y96. 20. Mainstone JC, Bruce AS, Golding TR. Tear meniscus measurement in the diagnosis of dry eye. Curr Eye Res 1996;15:653Y61. 21. Santodomingo-Rubido J, Wolffsohn JS, Gilmartin B. Comparison between graticule and image capture assessment of lower tear film meniscus height. Cont Lens Anterior Eye 2006;29:169Y73.
22. Johnson ME, Murphy PJ. The agreement and repeatability of tear meniscus height measurement methods. Optom Vis Sci 2005; 82:1030Y7. 23. Tomlinson A, Blades KJ, Pearce EI. What does the phenol red thread test actually measure? Optom Vis Sci 2001;78:142Y6. 24. Lamberts DW, Foster CS, Perry HD. Schirmer test after topical anesthesia and the tear meniscus height in normal eyes. Arch Ophthalmol 1979;97: 1082Y5. 25. Miller WL, Doughty MJ, Narayanan S, Leach NE, Tran A, Gaume AL, Bergmanson JP. A comparison of tear volume (by tear meniscus height and phenol red thread test) and tear fluid osmolality measures in non-lens wearers and in contact lens wearers. Eye Contact Lens 2004;30:132Y7. 26. Oguz H, Yokoi N, Kinoshita S. The height and radius of the tear meniscus and methods for examining these parameters. Cornea 2000;19:497Y500. 27. Patel S, Wallace I. Tear meniscus height, lower punctum lacrimale, and the tear lipid layer in normal aging. Optom Vis Sci 2006; 83:731Y9. 28. Kwong YM, Cho P. Tear meniscus height in normal and dry eyes: evaluation using the Topcon IMAGEnet System. Optom Today 2001;4124:28Y31. 29. Doughty MJ, Laiquzzaman M, Oblak E, Button N. The tear (lacrimal) meniscus height in human eyes: a useful clinical measure or an unusable variable sign? Cont Lens Anterior Eye 2002;25:57Y65. 30. Port MJA, Asaria TS. The assessment of human tear flow. J Br Contact Lens Assoc 1990;13:76Y82. 31. Pult H, Riede-Pult B. Comparison of subjective grading and objective assessment in meibography. Cont Lens Anterior Eye 2013;36:22Y7. 32. Srinivasan S, Menzies K, Sorbara L, Jones L. Infrared imaging of meibomian gland structure using a novel keratograph. Optom Vis Sci 2012;89:788Y94. 33. Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods 2012;9:671Y5. 34. Garcı´a-Resu´a C, Pena-Verdeal H, Lira M, Real Oliveira ME, Giraldez MJ, Yebra-Pimentel E. Comparison between three methods to value lower tear meniscus measured by image software. In: Filipe M, Martins-Costa PC, eds. 8th Iberoamerican Optics Meeting and 11th Latin American Meeting on Optics, Lasers, and Applications. Porto, Portugal: SPIE; 2013. 35. Korb DR. The tear filmVits role today and in the future. In: Korb D, Craig J, Doughty M, Guillon JP, Tomlinson A, Smith G, eds. The Tear Film: Structure, Function and Clinical Examination. Boston, MA: Butterworth-Heinemann; 2002:126Y92. 36. Khurana AK, Chaudhary R, Ahluwalia BK, Gupta S. Tear film profile in dry eye. Acta Ophthalmol (Copenh) 1991;69:79Y86. 37. Farris RL, Stuchell RN, Nisengard R. Sjogren’s syndrome and keratoconjunctivitis sicca. Cornea 1991;10:207Y9. 38. Farris RL, Gilbard JP, Stuchell RN, Mandel ID. Diagnostic tests in keratoconjunctivitis sicca. CLAO J 1983;9:23Y8. 39. Tomlinson A, Khanal S, Ramaesh K, Diaper C, McFadyen A. Tear film osmolarity: determination of a referent for dry eye diagnosis. Invest Ophthalmol Vis Sci 2006;47:4309Y15. 40. Messmer EM, Bulgen M, Kampik A. Hyperosmolarity of the tear film in dry eye syndrome. Dev Ophthalmol 2010;45:129Y38. 41. Tomlinson A, McCann LC, Pearce EI. Comparison of human tear film osmolarity measured by electrical impedance and freezing point depression techniques. Cornea 2010;29:1036Y41. 42. Lemp MA. Report of the National Eye Institute/Industry workshop on Clinical Trials in Dry Eyes. CLAO J 1995;21:221Y32.
Optometry and Vision Science, Vol. 91, No. 12, December 2014
Copyright © American Academy of Optometry. Unauthorized reproduction of this article is prohibited.
Tear Osmolarity and Tear MeniscusVGarcı´a-Resu´a et al. 43. Yildiz EH, Fan VC, Banday H, Ramanathan LV, Bitra RK, Garry E, Asbell PA. Evaluation of a new tear osmometer for repeatability and accuracy, using 0.5-microL (500-Nanoliter) samples. Cornea 2009;28:677Y80. 44. Versura P, Profazio V, Campos EC. Performance of tear osmolarity compared to previous diagnostic tests for dry eye diseases. Curr Eye Res 2010;35:553Y64. 45. Moore JE, Graham JE, Goodall EA, Dartt DA, Leccisotti A, McGilligan VE, Moore TC. Concordance between common dry eye diagnostic tests. Br J Ophthalmol 2009;93:66Y72. 46. Nichols KK, Nichols JJ, Mitchell GL. The lack of association between signs and symptoms in patients with dry eye disease. Cornea 2004;23:762Y70. 47. Ray WA, O’Day DM. Statistical analysis of multi-eye data in ophthalmic research. Invest Ophthalmol Vis Sci 1985;26:1186Y8. 48. Patel VD, Watanabe JH, Strauss JA, Dubey AT. Work productivity loss in patients with dry eye disease: an online survey. Curr Med Res Opin 2011;27:1041Y8. 49. McMonnies C, Ho A, Wakefield D. Optimum dry eye classification using questionnaire responses. Adv Exp Med Biol 1998;438:835Y8. 50. Glasson MJ, Stapleton F, Keay L, Sweeney D, Willcox MD. Differences in clinical parameters and tear film of tolerant and intolerant contact lens wearers. Invest Ophthalmol Vis Sci 2003;44:5116Y24. 51. Miller KL, Walt JG, Mink DR, Satram-Hoang S, Wilson SE, Perry HD, Asbell PA, Pflugfelder SC. Minimal clinically important difference for the ocular surface disease index. Arch Ophthalmol 2010;128:94Y101. 52. McMonnies CW. Key questions in a dry eye history. J Am Optom Assoc 1986;57:512Y7.
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53. Ogasawara K, Mitsubayashi K, Tsuru T, Karube I. Electrical conductivity of tear fluid in healthy persons and keratoconjunctivitis sicca patients measured by a flexible conductimetric sensor. Graefes Arch Clin Exp Ophthalmol 1996;234:542Y6. 54. Dunn G. Design and Analysis of Reliability Studies: The Statistical Evaluation of Measurement Errors. Oxford, NY: Oxford University Press; 1989. 55. Gilbard JP, Farris RL, Santamaria J, 2nd. Osmolarity of tear microvolumes in keratoconjunctivitis sicca. Arch Ophthalmol 1978;96:677Y81. 56. Yokoi N, Komuro A. Non-invasive methods of assessing the tear film. Exp Eye Res 2004;78: 399Y407. 57. Cermak JM, Krenzer KL, Sullivan RM, Dana MR, Sullivan DA. Is complete androgen insensitivity syndrome associated with alterations in the meibomian gland and ocular surface? Cornea 2003; 22:516Y21. 58. Schulze MM, Hutchings N, Simpson TL. The perceived bulbar redness of clinical grading scales. Optom Vis Sci 2009;86:1250Y8. 59. Peterson RC, Wolffsohn JS. Objective grading of the anterior eye. Optom Vis Sci 2009;86:273Y8. 60. Ozdemir M, Temizdemir H. Age- and gender-related tear function changes in normal population. Eye (Lond) 2010;24:79Y83.
Carlos Garcı´a-Resu´a ´ ptica y Optometrı´a Facultad de O Campus Vida Universidad de Santiago de Compostela 15782 Santiago de Compostela Galicia, Spain e-mail: [email protected]
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